Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
75 participants
INTERVENTIONAL
2009-06-30
2012-12-31
Brief Summary
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Detailed Description
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Convergent epidemiological and clinical observations have identified urate - a major antioxidant and the end product of purine metabolism in humans - as the first molecular predictor of both the risk and the progression of typical Parkinson's disease (PD). Among some 1600 early PD patients enrolled in prior clinical trials, those with baseline serum urate levels in the highest quintile (i.e., in the upper normal range) displayed a 40% slower rate of clinical (disability) progression compared to those with baseline urate at or below the median (with p\<0.000001 for trend across quintiles). Similarly, amongst those who underwent serial SPECT brain scans for changes in dopamine transporter (DAT) binding, those with higher baseline serum urate levels displayed a slower rate of radiographic progression (loss of striatal DAT). Moreover, urate levels in baseline cerebrospinal fluid (CSF) samples also correlate inversely with rates of clinical progression. Although this link between urate and a slower decline in PD appears reproducible and robust, the critical question of causality remains to be answered by a well-designed clinical trial. The biological plausibility of neuroprotection by urate strengthens the rationale for expedient pursuit of a trial. The availability of established pharmacological approaches to elevating urate makes such a trial feasible. In particular, inosine, an orally bioavailable, central nervous system (CNS)-penetrant purine precursor of urate, offers a practical strategy as it can readily elevate serum urate, has been widely consumed as a nutritional supplement, and has been administered chronically in several multi-year clinical trials for multiple sclerosis. Before embarking on a neuroprotection trial of inosine for PD, careful assessment of the safety, validity and methodology of this approach in PD patients is warranted.
Specific Aims:
The main goal of the study is to determine whether inosine is suitable for phase III evaluation of its ability to modify the rate of disability progression in PD. Specific primary aims entail the determination of the safety and tolerability of oral inosine, and its ability to elevate urate levels in serum or CSF; and the selection of an optimal dosing regimen. Secondary aims entail the further optimization of a possible phase III study design.
Methods:
A placebo-controlled double-blind dose-ranging randomized trial of inosine will be conducted in early PD. Ninety untreated subjects diagnosed with idiopathic PD and with a serum urate below the population mean (\~6 mg/dL) will be enrolled at 17 North American sites and randomized to one of three treatment groups (n=30): 1) placebo, 2) inosine dosed to produce a mild elevation in serum urate, and 3) inosine dosed to produce a moderate elevation. Tolerability, validity (urate elevation), dosage and symptomatic efficacy will be assessed after 12 weeks of treatment. Contingent on adequate tolerability and validity as assessed in this short-term analysis, the study will continue for 2 years total duration with 2 groups (placebo and a merged single inosine dosing group) or the original 3 to assess long-term tolerability and safety, which will focus on main known risks of urolithiasis and gouty arthritis and the theoretical risk of cardiovascular disease.
Significance:
This study will determine whether a phase III trial of inosine as a potential neuroprotectant in PD is warranted. If it is, then the present study could shorten substantially the lead time, and through optimization of key design features would enhance the likelihood of its safety and success.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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[A:]
Placebo to produce no urate elevation
Placebo
500 mg of inactive substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing adjusted algorithmically to parallel that in the inosine arms
[B:]
Inosine to produce a mild urate elevation
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a mildly elevated serum urate range of 6.1 - 7.0 mg/dL
inosine
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a mildly elevated serum urate range of 6.1 - 7.0 mg/dL
[C.]
Inosine to produce a moderate urate elevation
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a moderately elevated serum urate range of 7.1 - 8.0 mg/dL
inosine
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a moderately elevated serum urate range of 7.1 - 8.0 mg/dL
Interventions
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Placebo
500 mg of inactive substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing adjusted algorithmically to parallel that in the inosine arms
inosine
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a mildly elevated serum urate range of 6.1 - 7.0 mg/dL
inosine
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a moderately elevated serum urate range of 7.1 - 8.0 mg/dL
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Currently not taking or needing any treatment for PD other than an monoamine oxidase-B (MAO-B) inhibitor
* Age 30 or older at the time of PD diagnosis
* Diagnosis of PD made within past 3 years
* Serum urate ≤ 5.8 mg/dL at initial screening
Exclusion Criteria
* History of renal disease or certain cardiovascular problems within the past year
* Acidic urine (pH ≤ 5.0), uric acid, or urate crystalluria at screening
* Use of certain medications including co-enzyme Q, creatine, more than 50 IU of vitamin E daily, and more than 300 mg of vitamin C daily. (A standard daily multivitamin is permitted.)
* Use of anti-PD and other medications targeting central nervous system dopamine transmission
* Known unstable medical or psychiatric condition that may compromise participation in the study
* Women who are pregnant or lactating
30 Years
ALL
No
Sponsors
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Massachusetts General Hospital
OTHER
Harvard School of Public Health (HSPH)
OTHER
University of Rochester
OTHER
Michael J. Fox Foundation for Parkinson's Research
OTHER
The Parkinson Study Group
NETWORK
Responsible Party
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Michael Schwarzschild
Principal Investigator
Principal Investigators
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Michael A Schwarzschild, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Massachusetts General Hospital
Locations
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University of Southern California
Los Angeles, California, United States
Eastern Connecticut Neurology Specialists, LLC
Manchester, Connecticut, United States
Institute for Neurodegenerative Disorders
New Haven, Connecticut, United States
Parkinson's Disease and Movement Disorders Center of Boca Raton
Boca Raton, Florida, United States
Rush University Medical Center
Chicago, Illinois, United States
Ochsner Clinic Foundation
New Orleans, Louisiana, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Boston University Medical Center
Boston, Massachusetts, United States
Michigan State University
East Lansing, Michigan, United States
Struthers Parkinson's Center
Golden Valley, Minnesota, United States
Duke University School of Medicine
Durham, North Carolina, United States
University of Cincinnati
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
Butler Hospital Movement Disorder Program
Providence, Rhode Island, United States
Scott & White Hospital
Temple, Texas, United States
Countries
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References
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Schwarzschild MA, Macklin EA, Bakshi R, Battacharyya S, Logan R, Espay AJ, Hung AY, Bwala G, Goetz CG, Russell DS, Goudreau JL, Parashos SA, Saint-Hilaire MH, Rudolph A, Hare JM, Curhan GC, Ascherio A; Parkinson Study Group SURE-PD Investigators. Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial. Neurology. 2019 Oct 1;93(14):e1328-e1338. doi: 10.1212/WNL.0000000000008194. Epub 2019 Sep 4.
Parkinson Study Group SURE-PD Investigators; Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528.
Related Links
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Related Info
Other Identifiers
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INO-PD-P2-2008
Identifier Type: -
Identifier Source: org_study_id
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